JPS5888366A - Preparation of guanidine derivative - Google Patents

Abstract

PURPOSE:To prepare the titled compound in high yield, under mild conditions, by reacting N-cyano-methylamino-2'-chloroethylamino azomethine with 4(5)-methyl- 5(4)-mercaptomethylimidazole or its salt in acetone. CONSTITUTION:The guanidine derivative of formula III can be prepared by reacting N-cyano-methylamino-2'-chloroethylaminoazomethine of formulaIwith 4(5)-methyl-5(4)-mercaptomethylimidazole of formula II or its salt, preferably hydrochloride, in acetone solvent in the presence of a condensation agent (e.g. NaOH, alkali alcoholate, etc.). The azomethine compound of formulaIis obtained by reacting N-cyano-methylamino-ethyleneimino-azomethine of formula IV with a hydrogen chloride donor such as pyridine hydrochloride, in chloroform solvent. EFFECT:The reaction can be carried out without using expensive catalyst. USE:An extremely effective histamine antagonistic agent at H2 receptor.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides guanidine derivatives, particularly N-methyl-N-cyano-N-[2
The present invention relates to a method for producing ((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine.

Cimetidine [I] is known as a highly effective antagonist of histamine at the H2 receptor.

Conventionally, a method for synthesizing cimetidine 1 has been carried out by combining a compound represented by the formula: [wherein X is C1 or Br] and 4(5)-methyl-5(4)-mercaptometelimidazole represented by [■]: in an alcoholic solvent in the presence of an expensive phase transfer catalyst and sodium hydroxide (Japanese Patent Publication No. 54-40547), and
[1]) as IJum salt, and compound (formerly (however, X
=Br) in an alcohol solvent (Japanese Unexamined Patent Publication No. 180566/1983) has been proposed.

However, the yield of cimetidine [I] by these methods is extremely low, and it can hardly be said that they are industrial synthesis methods. The reason for this low yield is that when the above compound [old] is reacted with [111] in the presence of sodium hydroxide in an alcoholic solvent, the following formula [ff
]: Due to the by-product of the compound shown below.

The present invention solves the drawbacks of the above synthesis method, and is based on the following formula [■
]: CIcH2CH2NHCNHCH3[V ]CN and 4(5
)-Methyl-5(4)-mercaptomethylimidazole or a salt thereof, preferably with hydrochloric acid 1, in an acetone solvent in the presence of a condensing agent, thereby providing a method for obtaining the cimetidine of [I] above. .

According to the method of the present invention, by carrying out the reaction of compound [Vl and [1111] in an acetone solvent, cimetidine can be produced in high yield without producing any by-products under mild reaction conditions of room temperature and normal pressure. [■] can be obtained. The yield reaches 70 or more as shown in the examples below.

The reaction is preferably carried out under an inert atmosphere such as a stream of nitrogen.

As a condensing agent, an alkali hydroxide such as IJ hydroxide, potassium hydroxide, or an alkali alcoholade such as sodium ethoxide or potassium ethoxide is used, and an expensive catalyst as in the conventional method is not required. I don't.

Note that the azomethine compound [Vl
is N-cyano-methylamino-ethyleneimino-azomethine represented by the formula [■]: CN in a solvent, preferably chloroform,
It is obtained by the action of a hydrogen chloride donor such as hydrogen chloride or the hydrochloride of an organic tertiary amine, preferably pyridine hydrochloride. The thus obtained compound [Vl is substantially free of by-products and can be easily isolated and purified, making it extremely suitable as a starting material for the synthesis of cimetidine [T1].

Next, examples of the present invention will be described.

Example [A1 Synthesis of azomethine compound [Vl: Chloroform I
O, n/K N-cyano-methylamino-ethyleneimino-azomethine 100 me and pyridine hydrochloride 98 m
After 1 hour of stirring and raising the temperature to 50°C, the reaction solution was allowed to pass through and the solution F was distilled off. The residue was recrystallized from petroleum ether to give a thin plate (thickness 0
．． 2m) [manufactured by Merck & Co., Ltd.], and if the developing solution is ethyl acetate, it is detected at Rf=0.5. Detection is 5'16 F
When the eC11Ii/6H20 ethanol solution is sprayed and heated with a dryer, it turns reddish-yellow.

[B] Synthesis of cimetidine [I]: N-cyano-methylamino-2'-chloroethylamino-azomethine [Vl 65.4 my] obtained in [A] above
15(4)-methyl-4(5)-mercaptomethylimidazole fill] hydrochloride 67 tnf and sodium hydroxide 33, f were added to acetone 5-1, and after stirring at room temperature for 8 to 4 hours, the reaction solution was be allowed. The p liquid was distilled off and extracted with ethyl acetate and 2N aqueous sodium hydroxide solution. After treating the ethyl acetate phase with sulfur salt, the solvent is distilled off. The residue was transferred to a thin layer of Merck 60F254 (thickness 0.2
5m) (use methanol as the developing solution). After extracting the target product with acetone and distilling off the solvent, it was recrystallized from acetonitrile and ether to obtain cimetidine [I]7.
8. Get d'. Yield: 76 cm.

Melting point: 139-141℃ Infrared absorption spectrum: Matches the standard.

Patent applicant: Fujimoto Pharmaceutical Co., Ltd. Agent Patent Attorney Shinhachibe Miyazaki

Claims (1)

[Claims] (1) A method for producing a guanidine derivative represented by the formula: %, which comprises reacting a compound represented by the formula % with a compound represented by the formula or a salt thereof in an acetone solvent.